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Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D

Bile acids are required for proper absorption of dietary lipids, including fat-soluble vitamins. Here, we show that the dietary vitamins A and D inhibit bile acid synthesis by repressing hepatic expression of the rate-limiting enzyme CYP7A1. Receptors for vitamin A and D induced expression of Fgf15,...

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Autores principales: Schmidt, Daniel R., Holmstrom, Sam R., Fon Tacer, Klementina, Bookout, Angie L., Kliewer, Steven A., Mangelsdorf, David J.
Formato: Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863217/
https://www.ncbi.nlm.nih.gov/pubmed/20233723
http://dx.doi.org/10.1074/jbc.M110.116004
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author Schmidt, Daniel R.
Holmstrom, Sam R.
Fon Tacer, Klementina
Bookout, Angie L.
Kliewer, Steven A.
Mangelsdorf, David J.
author_facet Schmidt, Daniel R.
Holmstrom, Sam R.
Fon Tacer, Klementina
Bookout, Angie L.
Kliewer, Steven A.
Mangelsdorf, David J.
author_sort Schmidt, Daniel R.
collection PubMed
description Bile acids are required for proper absorption of dietary lipids, including fat-soluble vitamins. Here, we show that the dietary vitamins A and D inhibit bile acid synthesis by repressing hepatic expression of the rate-limiting enzyme CYP7A1. Receptors for vitamin A and D induced expression of Fgf15, an intestine-derived hormone that acts on liver to inhibit Cyp7a1. These effects were mediated through distinct cis-acting response elements in the promoter and intron of Fgf15. Interestingly, transactivation of both response elements appears to be required to maintain basal Fgf15 expression levels in vivo. Furthermore, whereas induction of Fgf15 by vitamin D is mediated through its receptor, the induction of Fgf15 by vitamin A is mediated through the retinoid X receptor/farnesoid X receptor heterodimer and is independent of bile acids, suggesting that this heterodimer functions as a distinct dietary vitamin A sensor. Notably, vitamin A treatment reversed the effects of the bile acid sequestrant cholestyramine on Fgf15, Shp, and Cyp7a1 expression, suggesting a potential therapeutic benefit of vitamin A under conditions of bile acid malabsorption. These results reveal an unexpected link between the intake of fat-soluble vitamins A and D and bile acid metabolism, which may have evolved as a means for these dietary vitamins to regulate their own absorption.
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spelling pubmed-28632172010-05-12 Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D Schmidt, Daniel R. Holmstrom, Sam R. Fon Tacer, Klementina Bookout, Angie L. Kliewer, Steven A. Mangelsdorf, David J. J Biol Chem Gene Regulation Bile acids are required for proper absorption of dietary lipids, including fat-soluble vitamins. Here, we show that the dietary vitamins A and D inhibit bile acid synthesis by repressing hepatic expression of the rate-limiting enzyme CYP7A1. Receptors for vitamin A and D induced expression of Fgf15, an intestine-derived hormone that acts on liver to inhibit Cyp7a1. These effects were mediated through distinct cis-acting response elements in the promoter and intron of Fgf15. Interestingly, transactivation of both response elements appears to be required to maintain basal Fgf15 expression levels in vivo. Furthermore, whereas induction of Fgf15 by vitamin D is mediated through its receptor, the induction of Fgf15 by vitamin A is mediated through the retinoid X receptor/farnesoid X receptor heterodimer and is independent of bile acids, suggesting that this heterodimer functions as a distinct dietary vitamin A sensor. Notably, vitamin A treatment reversed the effects of the bile acid sequestrant cholestyramine on Fgf15, Shp, and Cyp7a1 expression, suggesting a potential therapeutic benefit of vitamin A under conditions of bile acid malabsorption. These results reveal an unexpected link between the intake of fat-soluble vitamins A and D and bile acid metabolism, which may have evolved as a means for these dietary vitamins to regulate their own absorption. American Society for Biochemistry and Molecular Biology 2010-05-07 2010-03-16 /pmc/articles/PMC2863217/ /pubmed/20233723 http://dx.doi.org/10.1074/jbc.M110.116004 Text en © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles
spellingShingle Gene Regulation
Schmidt, Daniel R.
Holmstrom, Sam R.
Fon Tacer, Klementina
Bookout, Angie L.
Kliewer, Steven A.
Mangelsdorf, David J.
Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D
title Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D
title_full Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D
title_fullStr Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D
title_full_unstemmed Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D
title_short Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D
title_sort regulation of bile acid synthesis by fat-soluble vitamins a and d
topic Gene Regulation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863217/
https://www.ncbi.nlm.nih.gov/pubmed/20233723
http://dx.doi.org/10.1074/jbc.M110.116004
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